PEP07: A novel, brain penetrant oral CHK1 inhibitor for the treatment of AML and MCL (6th Annual DDR Inhibitors Summit 2023)
Bettice Chen, Kyla Grimshaw, Jack Cheng, Allen Lee, Mel Liu, Meriel Major, Bob Boyle, Hong-Ren Wang
ONIVYDE®
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Cell Cycle and DNA Damage Response
In the cell cycle, cyclin-dependent kinases (CDKs) are used throughout the whole process to regulate cell growth, DNA replication and cell division. There are several checkpoints throughout the cell cycle to detect incorrect messages or signals, such as DNA damage, improper spindle formation, etc., to ensure that the cell cycle can continue to operate.
DNA damage response (DDR) combines regulation of cell cycle progression with DNA repair to provide time for cell repair and prevent DNA damage from being permanently passed on to daughter cells. DNA damage can activate cell cycle checkpoints in the G1 phase, the S phase, and the G2/M transition to arrest the cell cycle and allow for DNA repair (see left figure). Therefore, the specific proteins associated with each checkpoint are targets for the development of small molecule inhibitors. These DDR-targeted inhibitors mainly increase DNA damage in the G1 and S phases of the cell cycle, or prevent repair in the G2 phase, promote cell mitosis, and ultimately lead to cell death or senescence.
DNA damage response (DDR) combines regulation of cell cycle progression with DNA repair to provide time for cell repair and prevent DNA damage from being permanently passed on to daughter cells. DNA damage can activate cell cycle checkpoints in the G1 phase, the S phase, and the G2/M transition to arrest the cell cycle and allow for DNA repair (see left figure). Therefore, the specific proteins associated with each checkpoint are targets for the development of small molecule inhibitors. These DDR-targeted inhibitors mainly increase DNA damage in the G1 and S phases of the cell cycle, or prevent repair in the G2 phase, promote cell mitosis, and ultimately lead to cell death or senescence.
Product Overview
In November 2020, PharmaEngine and UK-based Sentinel Oncology entered into an exclusive collaboration and license agreement for SOL-578 (PharmaEngine later renamed PEP07), a CHK1 inhibitor. The partnership includes cooperating R&D of GLP toxicology and IND enabling studies of PEP07. In September 2022, PharmaEngine exercised the option for a Worldwide Exclusive License Agreement for PEP07 from Sentinel Oncology.
CHK1 is the main regulator of DNA damage and replication checkpoints in cells. It plays a key role in regulating the cell cycle and in DNA damage repair, and can affect cell survival and apoptosis.
CHK1 has been found to be highly expressed in a variety of tumors, including hematological tumors and solid tumors. Moreover, tumor cells with high expression of CHK1 are more resistant to DNA damage reactions caused by radiotherapy, chemotherapy or other tumor treatments, promoting the generation of more malignant tumor cells, and can lead to the occurrence of drug resistance and tumor recurrence.
PEP07 is a potentially the best-in-class among all CHK1 medicines with features such as high kinase selectivity, brain penetrating and oral bioavailability. The main function is to trigger replication catastrophe which leads to apoptosis in the cancer cell during DNA damage. PEP07 has demonstrated significant single-agent activity in inhibiting cancer cell growth and shows R&D potential in oncology therapy.
Clinical Development
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Latest News
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2024/04/24
PharmaEngine announces first patient dosed in Phase I trial of PEP07 for solid tumor cancers
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2023/09/22
PharmaEngine announces TFDA approval of PEP07 Phase I clinical trial for solid tumor cancers
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2023/08/15
PharmaEngine announces first patient dosed in Phase I trial of PEP07 for hematological cancers